<i>Tetra</i>-Substituted Pyridinylimidazoles As Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and c‑Jun <i>N</i>‑Terminal Kinase 3 for Potential Treatment of Neurodegenerative Diseases

<i>Tetra</i>-substituted imidazoles were designed as dual inhibitors of c-Jun <i>N</i>-terminal kinase (JNK) 3 and p38α mitogen-activated protein (MAP) kinase. A library of 45 derivatives was prepared and evaluated in a kinase activity assay for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC<sub>50</sub> values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38α MAP kinase inhibitors are <b>6m</b> (IC<sub>50</sub>: JNK3, 18 nM; p38α, 30 nM) and <b>14d</b> (IC<sub>50</sub>: JNK3, 26 nM; p38α, 34 nM) featuring both excellent solubility and metabolic stability. They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntington’s disease.